The long-term goal of this project is to provide information useful in predicting conditions in which non-target vertebrates may be unusually susceptible (or resistant) to the toxic action of pesticides, or of other chemicals as a result of exposure to pesticides. This will be accomplished by research directed at identifying, measuring and modifying the dynamic relationships among critical biochemical pathways of metabolism and action in relation to the response of intact organisms. In the proposed research emphasis is placed on studies of interactions involving organophosphorus (OP) pesticides, primarily phosphorothionate insecticides. During this project year, studies will be initiated or continued which will address the following questions: (1) What are the compound, time and dosage characteristics under which animals become tolerant to anticholinesterase insecticides in relation to the development of reduced muscarinic receptors? (2) What are the kinetic characteristics of the multiple sites of biotransformation and target acceptor binding sites that will enable prediction of toxic interaction among compounds? (3) Will competition for non-specific hydrolases enhance the delayed neurotoxic action of certain OP compounds by non-neurotoxic compounds? (4) What is the mechanism of marked species difference in cholinesterase inhibitory potency of certain OP insecticides? (5) Are cell cultures a useful approach for gaining further insight into neurotoxicity and metabolism insecticides.